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Omapatrilat (also known as Vanlev; BMS-186716) is a novel investigational antihypertensive agent that acts as a potent dual inhibitor of the metalloproteases ACE (angiotensin converting enzyme) and NEP (neutral endopeptidase) with Ki values of 0.64 and 0.45 nM, respectively. Omapatrilat is heterocyclic dipeptide mimetic that has antihypertensive activity. NEP inhibition results in elevated natriuretic peptide levels, promoting natriuresis, diuresis, vasodilation, and reductions in preload and ventricular remodeling. The drug was promoted for possible uses in congestive heart failure.
Physicochemical Properties
| Molecular Formula | C19H24N2O4S2 |
| Molecular Weight | 408.53486 |
| Exact Mass | 408.117 |
| Elemental Analysis | C, 55.86; H, 5.92; N, 6.86; O, 15.67; S, 15.70 |
| CAS # | 167305-00-2 |
| PubChem CID | 656629 |
| Appearance | White to gray solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 724.2±60.0 °C at 760 mmHg |
| Flash Point | 391.8±32.9 °C |
| Vapour Pressure | 0.0±2.5 mmHg at 25°C |
| Index of Refraction | 1.645 |
| LogP | 1.65 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 6 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 27 |
| Complexity | 568 |
| Defined Atom Stereocenter Count | 4 |
| SMILES | O=C([C@@H]1CCC[C@](N21)([H])SCC[C@H](NC([C@@H](S)CC3=CC=CC=C3)=O)C2=O)O |
| InChi Key | LVRLSYPNFFBYCZ-VGWMRTNUSA-N |
| InChi Code | InChI=1S/C19H24N2O4S2/c22-17(15(26)11-12-5-2-1-3-6-12)20-13-9-10-27-16-8-4-7-14(19(24)25)21(16)18(13)23/h1-3,5-6,13-16,26H,4,7-11H2,(H,20,22)(H,24,25)/t13-,14-,15-,16-/m0/s1 |
| Chemical Name | (4S,7S,10aS)-4-((S)-2-mercapto-3-phenylpropanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid |
| Synonyms | BMS 186716; Vanlev; BMS186716; BMS-186716; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.(2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
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| ln Vitro | Omapatrilat (Ki=0.45, 25, 0.64, 250 nM) shows poor action against ECE1, but significant potency for NEP, NEP2, and ACE, as well as moderately strong activity against APP [1]. Simpatril (10 mg/kg) produces rapid and potent suppression of renal NEP and ACE for 24 hours, respectively, according to in vitro autoradiography utilizing the particular radioligands for NEP and ACE inhibitors, 125I-RB104 and 125I-MK351A, respectively[4]. | |
| ln Vivo | In numerous animal models with varying degrees of plasma renin activity, omapatrilat exhibits excellent blood pressure decrease. In a test using cynomolgus monkeys, it also dramatically increases urine sodium, ANP, and cGMP excretion. Between 10 and 24 hours, omapatrilat lowers mean arterial pressure (MAP) by around 40 mmHg below baseline. On day three, the systolic blood pressure is 38 mmHg lower when oral omapatrilat at 100 μM/kg is administered once daily as opposed to vehicle [2]. Omapatrilat is frequently utilized in experimental procedures pertaining to heart failure and hypertension. Omapatrilat, when taken orally over time, has been shown to improve endothelium independent vasorelaxation to ANP and decrease aortic leakiness and atheroma formation[3]. In rats, omapatrilat significantly reduces plasma ACE and increases plasma renin activity[4]. | |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion The absolute oral bioavailability of omapatrilat is 20% to 30% and the absorption is not affected by food intake. Metabolism / Metabolites Hepatic |
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| References |
[1]. Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy ofenzymes associated with bradykinin-mediated angioedema.Br J Pharmacol. 2008 Mar;153(5):947-55. [2]. Dual metalloprotease inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics asinhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem. 1997 May 23;40(11):1570-7. [3]. Endothelial permeability in vitro and in vivo: protective actions of ANP and omapatrilat in experimental atherosclerosis. Peptides. 2013 Oct;48:21-6. [4]. Antihypertensive and antihypertrophic effects of omapatrilat in SHR. Am J Hypertens. 2000 Oct;13(10):1110-6. |
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| Additional Infomation |
Omapatrilat is a dipeptide. Omapatrilat is an investigational drug that inhibits both neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). The inhibition of NEP elevates natriuretic peptide levels, increasing excretion of sodium in urine, dilating blood vessels, and reducing preload and ventricular remodeling. This drug from BMS was not approved by the FDA due to angioedema safety concerns. Omapatrilat is a vasopeptidase inhibitor with antihypertensive activity. Omapatrilat exerts its effect by inhibiting angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP). ACE inhibition results in inhibition of the renin-angiotensin-aldosterone system thereby leading to the reduction of vasoconstriction. Inhibition of NEP leads to the inhibition of hydrolyzation of a number of endogenous vasoactive peptides, such as bradykinin and substance P and as NEP is the principal enzyme degrading natriuretic peptides, NEP inhibition also results in an increase in natriuretic peptidase circulation. Ultimately both effects result in blood vessel relaxation. Drug Indication For the treatment of hypertension. Mechanism of Action Omapatrilat binds to both angiotensin converting enzyme and neutral endopeptidase. This results in a decrease renin-angiotensin-aldosterone production and increase natriuretic peptidase circulation. Pharmacodynamics Omapatrilat is used to treat hypertension. Vasopeptidase inhibitor that simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). Omapatrilat lowers blood pressure by inhibiting the action of the angiotensin converting enzyme (ACE), which causes blood vessels to constrict. But unlike other drugs, omapatrilat also inhibits another enzyme known as neutral endopeptidase (NEP), which helps blood vessels relax. Omapatrilat demonstrated greater reduction in blood pressure than the ACE inhibitor lisinopril in individuals with salt-sensitive hypertension who typically do not respond well to ACE inhibitors. |
Solubility Data
| Solubility (In Vitro) | DMSO : ≥ 31 mg/mL (~75.88 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 4.25 mg/mL (10.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 42.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.12 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4478 mL | 12.2390 mL | 24.4780 mL | |
| 5 mM | 0.4896 mL | 2.4478 mL | 4.8956 mL | |
| 10 mM | 0.2448 mL | 1.2239 mL | 2.4478 mL |